Pharmacokinetics, distribution, and excretion of 125I-labeled human plasma-derived-FVIIa and -FX with MC710 (FVIIa/FX mixture) in rats

Abstract

Introduction: MC710 is a mixture agent consisting of plasma-derived activated factor VII (FVIIa) and factor X (FX) at a weight ratio of 1:10 developed as a novel bypassing agent for the management of the bleeding of hemophilia patients with inhibitors. The pharmacokinetics, distribution, and excretion of (125)I-labeled-FVIIa ((125)I-FVIIa) and -FX ((125)I-FX) were studied in male rats after a single intravenous administration of (125)I-FVIIa or (125)I-FX combined with MC710.

Methods: (125)I-FVIIa or (125)I-FX was administered intravenously with MC710 to male rats in a single dosage (FVIIa 0.4 mg and FX 4 mg/kg body weight) and radioactivity and antigen levels in plasma were quantified for 24h. Urine and feces were sampled to study the excretion of radioactivity during 168 h after dosing. Whole-body autoradiography was performed to evaluate the qualitative distribution of radioactivity 168 h after dosing.

Results and conclusions: The half-life (t(1/2)α and t(1/2)β) of radioactivity and FVIIa antigen were 0.704 and 6.27 h, and 0.496 and 1.66 h, respectively and the area under the plasma concentration-time curve (AUC(0-∞)) of radioactivity and FVIIa antigen were 17,932 and 8671 ng·h/mL, respectively. The t(1/2) of radioactivity and FX antigen were 4.06 and 3.05 h, respectively, and the AUC(0-∞) of radioactivity and FX antigen were 320,143 and 395,794 ng·h/mL, respectively. About 80% of the administered dose of radioactivity was excreted in urine and feces by 168 h after administration. Tissue distribution experiments showed that FVIIa- and FX-related (125)I accumulated in bone and bone marrow, and disappeared slowly.